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Antidepressant Use in Pediatric Patients - October 15, 2004

In March 2004, the Food and Drug Administration (FDA) issued a Public Health Advisory concerning the use of antidepressant medications in which they called attention to reports of both suicidal ideation and suicide attempts in children taking antidepressant drugs for the treatment of major depressive disorder (MDD). In September 2004, a review of the existing data was completed by two FDA Advisory Committees. The FDA has now instructed the manufacturers of ALL antidepressants to revise the labeling for their products to include a boxed warning and expanded warning statements that alert healthcare providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents, and to include additional information about the results of pediatric studies. The FDA also informed manufacturers that a Patient Medication Guide (MedGuide), which will be given to patients receiving the drugs advising them of the risk and precautions, is appropriate for these drug products.

The risk of suicidality for these drugs was identified in a combined analysis of short-term (up to 4 months) placebo-controlled trials of nine antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs) and others, in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. A total of 24 trials involving over 4400 patients were included. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4%, compared to a rate of 2% in groups receiving placebo. No suicides occurred in these trials. Based on this data, the FDA has determined that the following points are appropriate for inclusion in the boxed warning:

Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with MDD and other psychiatric disorders.

Anyone considering the use of an antidepressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need.

Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior.

Families and caregivers should be advised to closely observe the patient and to communicate with the prescriber.

A statement regarding whether the particular drug is approved for any pediatric indication(s) and, if so, which one(s).

Among the antidepressants, only fluoxetine is approved for use in treating MDD in pediatric patients. Clomipramine, fluoxetine, fluvoxamine, and sertraline are approved for OCD in pediatric patients. None of the drugs is FDA approved for other psychiatric indications in children.

Pediatric patients being treated with antidepressants for any indication should be closely observed for clinical worsening, as well as agitation, irritability, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes (either increases or decreases). This monitoring should include daily observation by families and caregivers and frequent contact with the physician. It is also recommended that prescriptions for antidepressants be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

In addition to the boxed warning and other information in professional labeling on antidepressants, MedGuides are being prepared for all of the antidepressants to provide information about the risk of suicidality in children and adolescents for patients and their families and caregivers. MedGuides are intended to be distributed by the pharmacist with each prescription or refill of a medication.

The FDA plans to work closely with the manufacturers of all approved antidepressant products to optimize the safe use of these drugs and implement the proposed labeling changes and other safety communications in a timely manner.

Additional information can be found on the FDA website at: http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm#ssri, last accessed October 21, 2004.

Pronunciation:

(floo VOKS a meen)

Synonyms:

Luvox

Generic Available:

Yes

Canadian Brand Names:

Alti-Fluvoxamine; Apo-Fluvoxamine®; Luvox®; Novo-Fluvoxamine; Nu-Fluvoxamine; PMS-Fluvoxamine; Rhoxal-fluvoxamine

Use:

Treatment of obsessive-compulsive disorder (OCD) in children 8 years of age and adults

Use - Unlabeled/Investigational:

Treatment of major depression; panic disorder; anxiety disorders in children

Pregnancy Risk Factor:

Pregnancy Implications:

Nonteratogenic effects including respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypo- or hypertonia, hyper-reflexia, jitteriness, irritability, constant crying, and tremor have been reported in the neonate immediately following delivery after exposure to other SSRIs late in the third trimester. Adverse effects may be due to toxic effects of SSRI or drug discontinuation. In some cases, may present clinically as serotonin syndrome. There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if the potential benefit to the mother outweighs the possible risk to the fetus. If treatment during pregnancy is required, consider tapering therapy during the third trimester.

Lactation:

Enters breast milk/not recommended (AAP rates "of concern")

Contraindications:

Hypersensitivity to fluvoxamine or any component of the formulation; concurrent use with pimozide, thioridazine, mesoridazine, or cisapride; use of MAO inhibitors within 14 days

Warnings/Precautions:

Potential for severe reaction when used with MAO inhibitors - serotonin syndrome (hyperthermia, muscular rigidity, mental status changes/agitation, autonomic instability) may occur. May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Monitor for worsening of depression or suicidality, especially during initiation of therapy or with dose increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.

Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with MDD and other depressive disorders; consider risk prior to prescribing. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the child's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide should be dispensed with each prescription. Fluvoxamine is FDA approved for the treatment of OCD in children 8 years of age.

Has a low potential to impair cognitive or motor performance; caution operating hazardous machinery or driving. Use caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage, alcoholism, or concurrent therapy with other drugs which lower the seizure threshold. Use with caution in patients with hepatic or renal dysfunction and in elderly patients. May cause hyponatremia/SIADH. Use with caution in patients with renal insufficiency or other concurrent illness (cardiovascular disease). Use with caution in patients at risk of bleeding or receiving concurrent anticoagulant therapy, although not consistently noted, fluvoxamine may cause impairment in platelet function. May cause or exacerbate sexual dysfunction.

Adverse Reactions:

>10%:

Central nervous system: Headache (22%), somnolence (22%), insomnia (21%), nervousness (12%), dizziness (11%)

Gastrointestinal: Nausea (40%), diarrhea (11%), xerostomia (14%)

Neuromuscular & skeletal: Weakness (14%)

1% to 10%:

Cardiovascular: Palpitations

Central nervous system: Somnolence, mania, hypomania, vertigo, abnormal thinking, agitation, anxiety, malaise, amnesia, yawning, hypertonia, CNS stimulation, depression

Endocrine & metabolic: Decreased libido

Gastrointestinal: Abdominal pain, vomiting, dyspepsia, constipation, abnormal taste, anorexia, flatulence, weight gain

Genitourinary: Delayed ejaculation, impotence, anorgasmia, urinary frequency, urinary retention

Neuromuscular & skeletal: Tremors

Ocular: Blurred vision

Respiratory: Dyspnea

Miscellaneous: Diaphoresis

<1%: Acne, alopecia, anemia, angina, ataxia, bradycardia, delayed menstruation, dermatitis, dry skin, dysuria, extrapyramidal symptoms, hyponatremia, lactation, leukocytosis, nocturia, priapism, seizure, serotonin syndrome, SIADH, thrombocytopenia, urticaria

Postmarketing and/or case reports (causal relationship not established): Agranulocytosis, akinesia with fever, anaphylaxis, angioedema, aplastic anemia, Henoch-Schönlein purpura, hepatitis, neuropathy, pancreatitis, Stevens-Johnson syndrome, torsade de pointes, toxic epidermal necrolysis, transaminases increased, vasculitis, ventricular tachycardia

Overdosage/Toxicology:

Symptoms of overdose include drowsiness, nausea, vomiting, abdominal pain, tremor, sinus bradycardia, and seizures. A specific antidote does not exist. Treatment is supportive.

Drug Interactions:

Substrate (major) of CYP1A2, 2D6; Inhibits CYP1A2 (strong), 2B6 (weak), 2C8/9 (weak), 2C19 (strong), 2D6 (weak), 3A4 (weak)

Amphetamines: SSRIs may increase the sensitivity to amphetamines, and amphetamines may increase the risk of serotonin syndrome

Benzodiazepines: Fluvoxamine may inhibit the metabolism of alprazolam, diazepam, and triazolam resulting in elevated serum levels; monitor for increased sedation and psychomotor impairment

Beta-blockers: Fluvoxamine may inhibit the metabolism of metoprolol and propranolol resulting in cardiac toxicity; monitor for bradycardia, hypotension, and heart failure if combination is used; not established for all beta-blockers (unlikely with atenolol or nadolol due to renal elimination)

Buspirone: Fluvoxamine inhibits the reuptake of serotonin; combined use with a serotonin agonist (buspirone) may cause serotonin syndrome; fluvoxamine may also increase serum concentrations of buspirone

Carbamazepine: Fluvoxamine may inhibit the metabolism of carbamazepine resulting in increased carbamazepine levels and toxicity; monitor for altered carbamazepine response

Carvedilol: Serum concentrations may be increased; monitor carefully for increased carvedilol effect (hypotension and bradycardia)

Cisapride: Concurrent use is contraindicated

Clozapine: Fluvoxamine inhibits the metabolism of clozapine; adjust clozapine dosage downward or use an alternative SSRI

CYP1A2 inducers: May decrease the levels/effects of fluvoxamine. Example inducers include aminoglutethimide, carbamazepine, phenobarbital, and rifampin.

CYP1A2 inhibitors: May increase the levels/effects of fluvoxamine. Example inhibitors include amiodarone, ciprofloxacin, ketoconazole, norfloxacin, ofloxacin, and rofecoxib.

CYP1A2 substrates: Fluvoxamine may increase the levels/effects of CYP1A2 substrates. Example substrates include aminophylline, mexiletine, mirtazapine, ropinirole, theophylline, and trifluoperazine.

CYP2C19 substrates: Fluvoxamine may increase the levels/effects of CYP2C19 substrates. Example substrates include citalopram, diazepam, methsuximide, phenytoin, propranolol, and sertraline.

CYP2D6 inhibitors: May increase the levels/effects of fluvoxamine. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

Cyproheptadine: May inhibit the effects of serotonin reuptake inhibitors (fluvoxamine); monitor for altered antidepressant response; cyproheptadine acts as a serotonin agonist

Dextromethorphan: Fluvoxamine inhibits the metabolism of dextromethorphan; visual hallucinations occurred in a patient receiving this combination; monitor for serotonin syndrome

Haloperidol: Fluvoxamine may inhibit the metabolism of haloperidol and cause extrapyramidal symptoms (EPS); monitor patients for EPS if combination is utilized

HMG-CoA reductase inhibitors: Fluvoxamine may inhibit the metabolism of lovastatin and simvastatin resulting in myositis and rhabdomyolysis; these combinations are best avoided

Lithium: Patients receiving SSRIs and lithium have developed neurotoxicity; if combination is used, monitor for neurotoxicity

Loop diuretics: Fluvoxamine may cause hyponatremia; additive hyponatremic effects may be seen with combined use of a loop diuretic (bumetanide, furosemide, torsemide); monitor for hyponatremia

MAO inhibitors: Fluvoxamine should not be used with nonselective MAO inhibitors (isocarboxazid, phenelzine); fatal reactions have been reported; this combination should be avoided

Meperidine: Combined use with fluvoxamine theoretically may increase the risk of serotonin syndrome

Methadone: Fluvoxamine may increase serum concentrations of methadone; monitor for increased effect

Mexiletine: Clearance of mexiletine was reduced by 38% following coadministration with fluvoxamine. If used concurrently, mexiletine levels should be monitored.

Nefazodone: May increase the risk of serotonin syndrome with SSRIs

NSAIDs: Concomitant use of fluvoxamine and NSAIDs, aspirin, or other drugs affecting coagulation has been associated with an increased risk of bleeding; monitor.

Pimozide: Concurrent use is contraindicated

Phenothiazines: Fluvoxamine may inhibit metabolism of phenothiazines; concurrent use of agents associated with QT prolongation (thioridazine, mesoridazine) is contraindicated

Phenytoin: Fluvoxamine inhibits the metabolism of phenytoin and may result in phenytoin toxicity; monitor for phenytoin toxicity (ataxia, confusion, dizziness, nystagmus, involuntary muscle movement)

Propafenone: Serum concentrations and/or toxicity may be increased by fluoxetine; avoid concurrent administration

Quinidine: Serum concentrations may be increased with fluvoxamine; avoid concurrent use

Ritonavir: Combined use of fluvoxamine with ritonavir may cause serotonin syndrome in HIV-positive patients; monitor

Selegiline: SSRIs have been reported to cause mania or hypertension when combined with selegiline; this combination is best avoided. In addition, use with some SSRIs has been reported to cause serotonin syndrome. As an MAO type B inhibitor, the risk of serotonin syndrome may be less than with nonselective MAO inhibitors.

Serotonin reuptake inhibitors: Combined use with other drugs which inhibit the reuptake may cause serotonin syndrome; monitor patient for altered response with nefazodone; avoid sibutramine combination

Sibutramine: May increase the risk of serotonin syndrome with SSRIs

Sumatriptan (and other serotonin agonists): Concurrent use may result in toxicity; weakness, hyper-reflexia, and incoordination have been observed with sumatriptan and SSRIs. In addition, concurrent use may theoretically increase the risk of serotonin syndrome; includes sumatriptan, naratriptan, rizatriptan, and zolmitriptan.

Sympathomimetics: May increase the risk of serotonin syndrome with SSRIs

Tacrine: Fluvoxamine inhibits the metabolism of tacrine; use alternative SSRI

Tacrolimus: Fluvoxamine may inhibit the metabolism of tacrolimus; monitor for adverse effects; consider an alternative SSRI

Theophylline: Fluvoxamine inhibits the metabolism of theophylline; monitor for theophylline toxicity or use alternative SSRI

Tramadol: Fluvoxamine combined with tramadol (serotonergic effects) may cause serotonin syndrome; monitor

Trazodone: Fluvoxamine may inhibit the metabolism of trazodone resulting in increased toxicity; monitor

Tricyclic antidepressants Fluvoxamine inhibits the metabolism of tricyclic antidepressants (amitriptyline, desipramine, imipramine, nortriptyline) resulting is elevated serum levels; if combination is warranted, a low dose of TCA (10-25 mg/day) should be utilized

Tryptophan: Fluvoxamine inhibits the reuptake of serotonin; combination with tryptophan, a serotonin precursor, may cause agitation and restlessness; this combination is best avoided

Venlafaxine: Combined use with fluvoxamine may increase the risk of serotonin syndrome

Warfarin: Fluvoxamine may alter the hypoprothrombinemic response to warfarin; monitor

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol. Depressed patients should avoid/limit intake.

Food: The bioavailability of melatonin has been reported to be increased by fluvoxamine.

Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, kava kava (may increase risk of serotonin syndrome and/or excessive sedation).

Stability:

Protect from high humidity and store at controlled room temperature 15°C to 30°C (59°F to 86°F); dispense in tight containers

Mechanism of Action:

Inhibits CNS neuron serotonin uptake; minimal or no effect on reuptake of norepinephrine or dopamine; does not significantly bind to alpha-adrenergic, histamine or cholinergic receptors

Pharmacodynamics/Kinetics:

Absorption: Steady-state plasma concentrations have been noted to be 2-3 times higher in children than those in adolescents; female children demonstrated a significantly higher AUC than males

Distribution: Vd: ~25 L/kg

Protein binding: ~80%, primarily to albumin

Metabolism: Hepatic

Bioavailability: 53%; not significantly affected by food

Half-life elimination: ~15 hours

Time to peak, plasma: 3-8 hours

Excretion: Urine

Dosage:

Oral: Note: When total daily dose exceeds 50 mg, the dose should be given in 2 divided doses:

Children 8-17 years: Initial: 25 mg at bedtime; adjust in 25 mg increments at 4- to 7-day intervals, as tolerated, to maximum therapeutic benefit: Range: 50-200 mg/day

Maximum: Children: 8-11 years: 200 mg/day, adolescents: 300 mg/day; lower doses may be effective in female versus male patients

Adults: Initial: 50 mg at bedtime; adjust in 50 mg increments at 4- to 7-day intervals; usual dose range: 100-300 mg/day; divide total daily dose into 2 doses; administer larger portion at bedtime

Elderly: Reduce dose, titrate slowly

Dosage adjustment in hepatic impairment: Reduce dose, titrate slowly

Monitoring Parameters:

Mental status for depression, suicidal ideation, anxiety, social functioning, mania, panic attacks; akathisia, weight gain or loss, nutritional intake, sleep

Patient Education:

Take exactly as directed; do not increase dose or frequency. It may take 2-3 weeks to achieve desired results. Avoid alcohol, caffeine, and other prescription or OTC medications unless approved by prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience drowsiness, lightheadedness, impaired coordination, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, or anorexia (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruits, or fiber may help); diarrhea (buttermilk, yogurt, or boiled milk may help); postural hypotension (use caution when climbing stairs or changing position from lying or sitting to standing); or decreased sexual function or libido (reversible). Report persistent CNS effects (nervousness, restlessness, insomnia, anxiety, excitation, headache, sedation, seizures, mania, abnormal thinking); rash or skin irritation; muscle cramping, tremors, or change in gait; chest pain or palpitations; change in urinary pattern; or worsening of condition. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Dental Health: Effects on Dental Treatment:

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation) and abnormal taste. Problems with SSRI-induced bruxism have been reported and may preclude their use; clinicians attempting to evaluate any patient with bruxism or involuntary muscle movement, who is simultaneously being treated with an SSRI drug, should be aware of the potential association.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Although caution should be used in patients taking tricyclic antidepressants, no interactions have been reported with vasoconstrictors and fluvoxamine, a nontricyclic antidepressant which acts to increase serotonin

Dental Comment:

Problems with SSRI-induced bruxism have been reported and may preclude their use; clinicians attempting to evaluate any patient with bruxism or involuntary muscle movement, who is simultaneously being treated with an SSRI drug, should be aware of the potential association.

Mental Health: Child/Adolescent Considerations:

Children 8-17 years of age with obsessive-compulsive disorder (OCD) received 50-200 mg/day for 10 weeks (Riddle, 2001). One hundred twenty-eight children 6-17 years of age with social phobia, separation anxiety disorder, or generalized anxiety disorder, who had received psychological treatment for 3 weeks without improvement, received fluvoxamine up to 300 mg/day for 8 weeks (Research Unit, 2001).

"Fluvoxamine for the Treatment of Anxiety Disorders in Children and Adolescents. The Research Unit on Pediatric Psychopharmacology Anxiety Study Group,"N Engl J Med, 2001, 344(17):1279-85.

Riddle MA, Reeve EA, Yaryura-Tobias JA, et al, "Fluvoxamine for Children and Adolescents With Obsessive-Compulsive Disorder: A Randomized, Controlled, Multicenter Trial,"J Am Acad Child Adolesc Psychiatry, 2001, 40(2):222-9.

Dosage Forms:

Tablet: 25 mg, 50 mg, 100 mg

International Brand Names:

Alti-Fluvoxamine (CA); Apo-Fluvoxamine® (CA); Avoxin® (SI); Dumirox® (BE, ES, IT); Dumyrox® (PT); Faverin® (AU, GB, HK, IE, RO, SG, TH, TR); Favoxil® (IL); Felixsan® (AT); Fevarin® (BG, CZ, DE, DK, FI, HR, HU, IT, NL, NO, PL, RO, RU, SE); Flox-ex® (CH); Floxyfral® (AT, BE, CH, DE, FR, LU); Fluvohexal® (DE); Fluvoxadura® (DE); Fluvoxamina Geminis® (ES); Fluvoxamin AL® (DE); Fluvoxamin beta® (DE); Fluvoxamine® (GB); Fluvoxamine Maleate® (GB); Fluvoxamin-neuraxpharm® (DE); Fluvoxamin-ratiopharm® (DE); Fluvoxamin Stada® (DE); Fluvoxamin-TEVA® (DE); Fluvoxin® (IN, TH); Luvox® (AR, AU, BR, CA, CL, CO, CR, GT, HN, ID, MX, PA, SV, ZA); Maveral® (IT); Novo-Fluvoxamine (CA); Nu-Fluvoxamine (CA); PMS-Fluvoxamine (CA); Rhoxal-fluvoxamine (CA); Voxamin® (CO)

References

"American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk,"Pediatrics, 2001, 108(3):776-89.

de Vries MH, Raghoebar M, Mathlener IS, et al, "Single and Multiple Oral Dose Fluvoxamine Kinetics in Young and Elderly Subjects,"Ther Drug Monit, 1992, 14(6):493-8.

"Fluvoxamine for the Treatment of Anxiety Disorders in Children and Adolescents. The Research Unit on Pediatric Psychopharmacology Anxiety Study Group,"N Engl J Med, 2001, 344(17):1279-85.

Grimsley SR and Jann MW, "Paroxetine, Sertraline, and Fluvoxamine: New Selective Serotonin Reuptake Inhibitors,"Clin Pharm, 1992, 11(11):930-57.

Mokhlesi B, Leikin JB, Murray P, et al, "Adult Toxicology in Critical Care: Part II: Specific Poisonings,"Chest, 2003, 123(3):897-922.

Roose SP, Glassman AH, Attia E, et al, "Comparative Efficacy of Selective Serotonin Reuptake Inhibitors and Tricyclics in the Treatment of Melancholia,"Am J Psychiatry, 1994, 151(12):1735-9.

Wynn RL, "New Antidepressant Medications,"Gen Dent, 1997, 45(1):24-8.

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